Chronic lymphocytic leukemia (CLL) is an incurable neoplasm of the blood and is one of the most common B-cell malignancies in Caucasians in the United States. It has a strong genetic contribution to etiology, with one of the highest familial risks of disease among cancers. During the initial funding period, we have made substantial contributions to the genetic etiology of CLL through genome-wide association (GWA) studies and linkage studies. We have identified and confirmed susceptibility loci of CLL in the IRF8 gene on chromosome 16q24.1, as well as within the HLA region on chromosome 6p21.3. We also replicated previous GWA findings, including those within the IRF4 gene. One striking feature of our work and others is that several of the GWA findings appear to act in determining B-cell development (e.g., IRF4./IRF8). Further, our finding within the HLA region was only observed in our homogenous sample of familial CLL cases. In this renewal application, we take our GWA findings to the next step to further refine the location of the associated signals and to expand upon IRF4/IRF8 findings. Specifically, we propose to (Aim1) identify and validate new genetic variants of CLL risk by comprehensively genotyping genetic variants in genes related to IRF4/IRF8 genes. (Aim 2) to characterize our IRF8 region located on chromosome 16q24.1 through targeted deep sequencing and validation in larger sample of CLL cases and controls. (Aim 3) to characterize our HLA region located on chromosome 6p21.3 in discovery and validation samples of familial CLL cases and controls. We will carry-out our Aims using our unique ongoing resource of high-risk CLL pedigrees that are collected through the Genetic Epidemiology of CLL (GEC) Consortium led by Drs. Slager and Caporaso, as well as the Mayo Clinic CLL case-control study, Mayo Clinic Biobank, and the InterLymph Consortium. Our proposed application is the logical next step following a GWA study, and given our preliminary data, it has a high probability of success. We have a strong collaborative multicenter, multidisciplinary team of investigators who have the combined expertise to successfully carry out the Aims of this proposal. At the completion of this project, we expect to identify additional novel loci influencing CLL risk that could not have been identified through GWA studies. We will also provide a more thorough evaluation of our GWA loci in order to further refine the location of the associated signal. Collectively, our findings will provide for a better understanding of CLL pathobiology and may lead to novel therapeutic approaches to treating CLL and improve our counseling to relatives of CLL patients.